Calcitonin Gene-Related Peptide (CGRP)-Targeted Monoclonal Antibodies and Antagonists in Migraine: Current Evidence and Rationale.

Calcitonin gene-related peptide (CGRP), a 37 amino-acid neuropeptide found mostly in peptidergic sensory C-fibers, has been suggested to be implicated in the pathogenesis of migraine, which is one of the most common neurological disorders seen in medical practice, affecting almost 16% of the US population. While previously thought to be a vascular condition, migraine attacks are the result of neurogenic inflammation and peripheral/central sensitization through dysfunctional activation of the trigeminovascular system. To date, two classes of therapeutic agents have been developed to interrupt the function of CGRP: CGRP-targeted monoclonal antibodies (mAbs) and small-molecule antagonists (gepants). There are currently four CGRP-targeted mAbs and three gepants that are US Food and Drug Administration (FDA) approved for the treatment of migraine. Multiple phase II and III studies have established the efficacies and tolerability of these treatments. Previously, we reviewed the fundamental role of CGRP in migraine pathogenesis. Here, we discuss in depth the clinical evidence (randomized controlled trials and real-world studies), safety, and tolerability of CGRP-targeted mAbs and gepants for treating migraine.

Anti-CGRP and anti-CGRP receptor monoclonal antibodies as antimigraine agents. Potential differences in safety profile postulated on a pathophysiological basis.

Calcitonin gene-related peptide (CGRP) is a peptide neurotransmitter with potent vasodilating properties. CGRP is believed to play a primary role in the pathogenesis of migraine. As such, CGRP and its receptors are obvious druggable targets for novel anti-migraine agents. While the development of small-molecule CGRP receptor antagonists started first, none of these agents is yet available in clinical practice. Conversely, both anti-CGRP and anti-CGRP receptor monoclonal antibodies (mABs) completed clinical development, and the first representatives of these 2 classes are available on the market. MABs are approved for prevention of migraine attacks in chronic or episodic migraine, involving long-term treatments. In light of the physiological role exerted by CGRP in the regulation of vascular tone, the potential risks of a long-term inhibition of CGRP functions raised diffuse concerns. These concerns were correctly addressed by the anti-CGRP receptor mABs erenumab with a 5-year open-label clinical trial; however, this study is currently ongoing and results are not yet available, leaving some uncertainty on the profile of erenumab long-term safety. Similar concerns can be raised with direct anti-CGRP mABs, which entrap the peptide preventing receptor activation. However, evidence exists that plasma CGRP is detectable in patients chronically treated with anti-CGRP mABs. Assuming that plasma CGRP is an indirect marker of peptide levels at the vascular receptor sites, such residual CGRP would maintain a physiological level of receptor stimulation, in spite of a well-established anti-migraine activity of the mABs. This might represent a potential advantage in the safety profile of anti-CGRP mABs, but it needs to be confirmed and expanded with data on free plasma CGRP.

Antigens and Antibodies in Disease With Specifics About CGRP Immunology.

Growth in knowledge about calcitonin gene-related peptide (CGRP) in the pathophysiology of migraine brought CGRP antagonism to headache medicine. Failures in development of small molecule CGRP receptor antagonists and increasing knowledge and use of monoclonal antibodies (mAbs) in medicine led to the breakthrough development of large molecule anti-CGRP mAbs: eptinezumab, erenumab, fremanezumab, and galcanezumab. This specifics about CGRP immunology aims to outline: (1) knowledge needed for CGRP antagonism and (2) developmental issues of specific CGRP antagonists for provider use. This clinically oriented review documents IgG structure and function; state of the art of monoclonal IgG production and ligand-antigen-antibodies in migraine therapeutics contributing to immunogenic risks and off-target toxicities. Specifics to CGRP ligand, receptor, antagonism, and molecules, small and large, complete this review. Completion will facilitate assessment of the similarities, differences, and application of the forthcoming anti-CGRP receptor and ligand antagonists for patients.

The Biology of Monoclonal Antibodies: Focus on Calcitonin Gene-Related Peptide for Prophylactic Migraine Therapy.

Calcitonin gene-related peptide (CGRP) is 37-amino-acid neuropeptide, crucially involved in migraine pathophysiology. Four monoclonal antibodies (mAbs) targeting the CGRP pathway are currently under evaluation for the prevention of episodic and chronic migraine: eptinezumab (ALD403), fremanezumab (TEV-48125), galcanezumab (LY2951742), and erenumab (AMG334). As reviewed in this article, all 4 antibodies have been proven effective, tolerable, and safe as migraine prophylactic treatments in phase II clinical trials. The mean decrease in migraine days per month was between 3.4 and 6.3 days/month after 8 to 12 weeks of treatment, and the placebo subtracted benefit ranged from 1 to 2.18 days. Notably, up to 32% of subjects experienced total migraine freedom after drug administration. Substance class-specific adverse events and treatment-related serious adverse event did not occur. Further long-term and large-scale trials are currently under way to verify the safety and efficacy profile of mAbs. In particular, the potential risk of vascular adverse events and the role of anti-drug antibodies deserve special attention. Anti-CGRP peptide and anti-CGRP receptor antibodies are the first effective treatments, which were specifically developed for the prevention of migraine. Their site of action in migraine prevention is most likely peripheral due to large molecule size, which prevents the penetration through the blood-brain barrier and thereby shows that peripheral components play a pivotal role in the pathophysiology of a CNS disease.